Structure-based thermodynamic analysis of the dissociation of protein phosphatase-1 catalytic subunit and microcystin-LR docked complexes

The relationship between the structure of a free ligand in solution and the structure of its bound form in a complex is of great importance to the und erstanding of the energetics and mechanism of molecular recognition and com plex formation. In this study, we use a structure-based thermodynamic appro ach to study the dissociation of the complex between the toxin microcystin- LR (MLR) and the catalytic domain of protein phosphatase-l (PP-lc) for whic h the crystal structure of the complex is known. We have calculated the the rmodynamic parameters (enthalpy, entropy, heat capacity, and free energy) f or the dissociation of the complex from its X-ray structure and found the c alculated dissociation constant (4.0 x 10(-11)) to be in excellent agreemen t with the reported inhibitory constant (3.9 x 10(-11)). We have also calcu lated the thermodynamic parameters for the dissociation of 47 PP-lc:MLR com plexes generated by docking an ensemble of NMR solution structures of MLR o nto the crystal structure of PP-lc. In general, we observe that the lower t he root-mean-square deviation (RMSD) of the docked complex (compared to the X-ray complex) the closer its free energy of dissociation (Delta G(d)(o)) is to that calculated from the X-ray complex. On the other hand, we note a significant scatter between the Delta G(d)(o) and the RMSD of the docked co mplexes. We have identified a group of seven docked complexes with Delta G( d)(o) values very close to the one calculated from the X-ray complex but wi th significantly dissimilar structures. The analysis of the corresponding e nthalpy and entropy of dissociation shows a compensation effect suggesting that MLR molecules with significant structural variability can bind PP-lc a nd that substantial conformational flexibility in the PP-1c:MLR complex may exist in solution.